temocapril-hydrochloride and Kidney-Failure--Chronic

To assess the renal benefits of combined angiotensin-converting enzyme inhibition and alpha(1)-adrenergic antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone and in combination with doxazosin (DOX) in spontaneously hypertensive rats (SHR)/Izumo rats with renal ablation. Five-Sixths-nephrectomized rats were assigned to receive TMP (10 mg/kg/day) (TMP group), TMP plus DOX (2 mg/kg/day) (TMP+DOX group), or vehicle (control group) orally for 12 weeks. Both systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) in the control group progressively increased during the experimental period and were significantly higher than in sham-operated rats. Treatment with either TMP or TMP plus DOX had similar antihypertensive effects in this rat model. Twelve weeks after initiation of treatment, the SBP values in the control, TMP, and TMP+DOX groups were 265+/-8, 157+/-4, and 163+/-3 mmHg, respectively, in comparison with 233+/-4 mmHg in sham-operated rats (p<0.0001 control vs. sham, p<0.001 TMP vs. control, p<0.001 TMP+DOX vs. control). UalbV, serum creatinine (Scr), blood urea nitrogen (BUN), and heart weight/body weight (HW/BW) ratio were significantly lower in the TMP and TMP+DOX groups than in the control group (UalbV: p<0.05; Scr: p<0.01; [BUN, HW/BW ratio]: p<0.0001; and [UalbV, Scr, BUN, HW/BW ratio]: p<0.0001 vs. control, respectively). The index of glomerular sclerosis (IGS) and relative interstitial volume (RIV) were significantly lower in the TMP+DOX group than in the control group (IGS: p<0.05; RIV: p<0.01). Especially, UalbV, IGS, and RIV were significantly better in the TMP+DOX group than in the TMP group ([IGS, RIV]: p<0.05; UalbV: p<0.01). These results suggest that simultaneous administration of TMP and DOX provides greater renoprotective effects than administration of TMP alone.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Doxazosin; Drug Therapy, Combination; Hypertension; Kidney; Kidney Cortex; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Rats; Rats, Inbred SHR; Sclerosis; Thiazepines

To assess the renal benefits of combined angiotensin-converting enzyme inhibition and calcium antagonism, we studied the antihypertensive and renoprotective effects of temocapril (TMP) alone or in combination with azelnidipine (AZN) in a spontaneously hypertensive rat (SHR) remnant kidney model of chronic renal failure. Male 5/6-nephrectomized SHR/Izumo rats were randomly assigned to receive vehicle (control group), TMP (TMP group; 10 mg x kg(-1) x day(-1)), AZN (AZN group; 3 mg x kg(-1) x day(-1)), or both (TMP+AZN group) orally for 12 weeks. Systolic blood pressure (SBP) and urinary excretion of albumin (UalbV) were measured every 2 weeks. At the end of the experiment, serum creatinine (Scr), heart weight (HW), and blood urea nitrogen (BUN) levels were measured and the remnant kidneys were examined to determine the index of glomerular sclerosis (IGS). SBP and UalbV in the control group increased progressively throughout the experimental period. TMP, AZN, and TMP+AZN blocked the development of hypertension. TMP+AZN did not enhance the antihypertensive effects of either TMP or AZN used singly. TMP, AZN, and TMP+AZN all significantly decreased the UalbV, Scr, BUN, and HW/body weight (BW) ratio. The level of UalbV and the HW/BW ratio in the TMP+AZN group were significantly lower than those in the TMP and AZN groups, and the level of Scr in the TMP+AZN group was significantly lower than that in the TMP group. TMP, AZN, and TMP+AZN all significantly protected against an increase in the IGS. The IGS in the TMP+AZN group was significantly lower than that in the TMP and AZN groups. These results indicate that both TMP and AZN have antihypertensive and renoprotective effects in this model. They also suggest that simultaneous administration of TMP and AZN provides greater renoprotective effects than TMP alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azetidinecarboxylic Acid; Calcium Channel Blockers; Dihydropyridines; Drug Therapy, Combination; Hypertension; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Protective Agents; Rats; Rats, Inbred SHR; Thiazepines

The current study was undertaken to compare the organ protective effects of an angiotensin-converting enzyme inhibitor, temocapril, with those of an angiotensin II type 1 receptor antagonist, CS-866 (olmesartan medoxomil), alone or combined, in the remnant kidney model of rats. Eight-week-old spontaneously hypertensive male rats were subjected to five-sixths nephrectomy. At the age of 10 weeks, the rats were randomly allocated to groups that received two doses of CS-866 (CS-L, 3 mg/kg/day; CS-H, 10 mg/kg/day), temocapril (TEM, 10 mg/kg/day), CS-866 (3 mg/kg/day) plus temocapril (10 mg/kg/day), or a vehicle alone (untreated control group). Systolic blood pressure (SBP) and urinary protein excretion (UprotV) were measured every 2 weeks. When the rats were 18 weeks old, biochemical measurement and histologic examination were performed. All the drug treatments significantly reduced SBP, UprotV, glomerular sclerosis index (GSI), relative interstitial volume (RIV), and heart weight. The hypotensive effects were on the order of combination therapy > CS-H = TEM > CS-L. Correlational analysis was based on the values for SBP and UprotV derived from the average of values obtained when the rats were 12 to 18 weeks of age. UprotV, GSI, and RIV were found to be highly correlated with SBP among the individual rats pooled from all the groups, and the correlation was maintained among the group means. A similar correlation was found between heart weight and SBP. The results suggest that the organ protective effects of temocapril, CS-866, and combination therapy are closely related to the magnitude of their antihypertensive effects.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Drug Therapy, Combination; Imidazoles; Kidney Failure, Chronic; Male; Olmesartan Medoxomil; Peptidyl-Dipeptidase A; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Tetrazoles; Thiazepines

The insulin resistance state is common in humans and animals with chronic renal failure. We investigated the effects of troglitazone, an insulin sensitizer, on blood pressure and nephropathy in the remnant kidney model of spontaneously hypertensive rats (SHR).. Eight-week-old male SHR were subjected to five-sixth nephrectomy. At the age of 10 weeks, the rats were randomly allocated to groups that received troglitazone (70 mg/kg per day); the angiotensin converting enzyme inhibitor temocapril (10 mg/kg per day); troglitazone (70 mg/kg per day) plus temocapril (10 mg/kg per day), or a vehicle alone as an untreated control group. Systolic blood pressure (SBP) and urinary protein excretion were measured every 2 weeks. At the age of 22 weeks, biochemical measurements and histological examination were performed.. Blood glucose, glycosylated hemoglobin and body weight were similar in the four groups. SBP, serum creatinine and glomerular sclerosis index were significantly reduced in all treated groups compared with those in the control group. Urinary protein excretion, glomerular volume and aortic media thickness were significantly decreased in temocapril-treated rats and troglitazone plus temocapril-treated rats compared with those in control rats. Although antihypertensive effects of troglitazone were minute compared with those of temocapril or troglitazone plus temocapril, there was no significant difference between the glomerular sclerosis indices in these three drug-treated groups.. The results suggest that troglitazone has renoprotective effects in this rat model. These effects might be due to the inhibition of growth factors rather than to the minute hypotensive effect, although the mechanism remains to be elucidated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Chromans; Humans; Hypertension; Hypoglycemic Agents; Insulin Resistance; Kidney; Kidney Failure, Chronic; Male; Proteinuria; Rats; Rats, Inbred SHR; Thiazepines; Thiazoles; Thiazolidinediones; Troglitazone

To assess the chronic antihypertensive and renal protective effects of the specific angiotensin II receptor antagonist, CS-866, in the remnant kidney model of chronic renal failure, we administered it alone or in combination with temocapril, an angiotensin converting enzyme inhibitor, to 5/6 nephrectomized spontaneously hypertensive rats (SHR) for 8 weeks. At the age of 10 weeks, 5/6 nephrectomized SHR were allocated to receive two doses of CS-866 (CS-3; 3 mg/kg/day, or CS-10; 10 mg/kg/day), temocapril (TEM; 10 mg/kg/day), a combination of CS-866 (3 mg/kg/day) and temocapril (10 mg/kg/day) or the vehicle alone via oral gavage for 8 weeks. Systolic blood pressure (SBP) and urinary protein excretion (UprotV) were measured every two weeks. At the age of 18 weeks, the rats were decapitated and the blood, remnant kidney, aorta and heart were collected and used for biochemical measurements and histopathological studies. There was no significant difference in body weight among the groups during the study. All drug treatments significantly reduced SBP, UprotV, glomerular sclerosis index (GSI), relative interstitial volume (RIV) and the heart weight to body weight ratio. The hypotensive effects were in the order of combination therapy > CS-10 = TEM > CS-3. For correlational analysis, we used values for SBP and UprotV derived from the average of values in rats over the age of 12 weeks through 18 weeks. UprotV, GSI and RIV were found to be highly correlated with SBP among the individual rats pooled from all groups (r = 0.511, r = 0.754, r = 0.817, respectively) and the correlation was maintained among the group means (r = 0.945, r = 0.989, r = 0.918, respectively). Furthermore, the heart weight to body weight ratio was found to be highly correlated with SBP among the individual rats pooled from all groups (r = 0.923) and the correlation was maintained among the group means (r = 0.996). We conclude that organ protective effects of CS-866, TEM, or combination therapy are closely related to the magnitude of their antihypertensive effects.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Disease Progression; Drug Therapy, Combination; Hypertension; Imidazoles; Kidney Failure, Chronic; Male; Nephrectomy; Olmesartan Medoxomil; Rats; Rats, Inbred SHR; Tetrazoles; Thiazepines